Bone is an extremely dynamic tissue that undergoes remodeling throughout life. Control of bone homeostasis is achieved through a complex combination of influences involving numerous cytokines, growth factors, steroid hormones and various calcitrophic molecules. These multi-functional effector molecules unite to regulate osteoclastic bone resorption and osteoblastic bone formation. Any disequilibrium in the control of osteoclasts and osteoblasts can lead to a variety of bone diseases in which inappropriate bone homeostasis is manifest. Osteopetrosis is caused by a heterogeneous group of congenital bone diseases that are characterized by a generalized increase in skeletal mass resulting from inadequate osteoclastic bone resorption. To date, the precise genetic control of osteoclast function remains inadequately understood and improved treatment of bone disease awaits a further elucidation of the complex control mechanisms of bone homeostasis. The objective of the proposed research is to examine the genetic control of osteoclast function with the use of an animal model of flawed bone resorption, the op osteopetrotic rat. The specific aims of this project are to 1) sequence functional candidate genes within the 0.51 cM genetic critical region to identify the gene responsible for osteopetrosis in the op rat. 2) validate that the genetic mutation identified within the op critical region is indeed responsible for the osteopetrosis and to begin to characterize the mechanisms of action whereby osteoclast function is compromised. Data from this project may reveal novel mechanisms in the control pathways of bone homeostasis that are relevant to numerous human bone diseases. Identification of the molecular mechanisms of failed bone homeostasis may reveal additional molecular therapeutic targets that can be pursued to improve the clinical treatment of a myriad of human bone diseases such as osteopetrosis, osteoporosis and rheumatoid arthritis.